Deep Neutropenia Research Articles

MEK-kinase Inhibitor as a treatment option for hairy cell leukemia

Introduction. Hairy cell leukemia (HCL) is a chronic indolent B–cell lymphoproliferative disease with a good response to treatment in most cases. However, despite successful treatment, there remains a group of patients with a resistant/recurrent course of the disease, a short remission after treatment, and with contraindications to standard therapy. The use of the RASRAF- MEK-ERK pathway inhibitor in the V600E marker mutation of the BRAF gene may prove to be an effective treatment option for complicated/resistant cases of HCL.Aim — to present the results of the use MEK-kinase inhibitor trametinib in the treatment of HCL.Main findings. The MEK-kinase inhibitor trametinib was used at a dose of 1 mg/day for 3 months in three patients. In two patients trametinib was used as preliminary stage before the main course of treatment with cladribine. In one patient with a resistant/relapsing course of HCL, trametinib monotherapy made it possible to achieve a good partial remission, and the treatment continues without a decrease in the quality of life.Conclusion. Trametinib can be used as a preliminary stage before analogous purine treatment in patients with HCL without the BRAF V600E mutation, in a case of deep neutropenia or infectious complications, and as the main antitumor therapy in patients with resistant/recurrent HCL. Trametinib is effective in the absence of the MAP2K1 mutations. Trametinib monotherapy can be effective at a reduced dosage (1 mg/day or 1 mg every other day).

ДИНАМИКА ПОКАЗАТЕЛЕЙ ПЕРИФЕРИЧЕСКОЙ КРОВИ В РАЗЛИЧНЫЕ ПЕРИОДЫ ТЕЧЕНИЯ ХРОНИЧЕСКОЙ ЛУЧЕВОЙ БОЛЕЗНИ, ВЫЗВАННОЙ РАДИАЦИОННЫМ ВОЗДЕЙСТВИЕМ С РАЗЛИЧНОЙ МОЩНОСТЬЮ ДОЗЫ

Purpose: To study the effect of the radiation dose rate on the dynamics of peripheral blood indicators in various periods of chronic radiation syndrome (CRS), which developed as a result of professional prolonged radiation exposure in a cohort of former employees of the Mayak plant who underwent inpatient examination at the clinic of the A.I. Burnazyan Federal Medical Biophysical Center of the FMBA of Russia in the period up to 1995. Material and methods: The study of the dynamics of absolute peripheral blood indices in former employees of Mayak plant who were exposed to prolonged industrial radiation with a dose rate of less than 0.001 Gy/day (25 people), 0.003‒0.007 Gy/day (12 people) and 0.008‒0.07 G/day (15 people) during the periods of formation, outcomes and immediate, as well as long-term consequences of CRS. Statistical processing of the material was performed using the IBM SPSS Statistics software package 23.0 using the Kruskal–Wallis criteria and the Mann–Whitney U-test for independent samples. The results obtained were considered statistically reliable at p < 0.05. Results: In a group of patients irradiated with a dose rate of 0.008‒0.07 Gy/day during the periods of formation, as well as the outcomes and immediate consequences of CRS, platelet-, leuco- and deep neutropenia were noted. A decrease in the number of erythrocytes and hemoglobin was detected only in the period of outcomes and immediate consequences. The development of agranulocytosis and anemic syndrome are signs that distinguish the course of CRS in this group of patients from the clinical picture of typical CRS. In the period of long-term consequences, 60 % of patients (9 out of 15) developed oncohematological diseases. At an irradiation power of 0.003‒0.007 Gy/day anemic syndrome was found in 4 out of 12 patients. Leukopenia was observed in the periods of outcomes and immediate consequences. Granulocytopenia was detected in all three periods of the course of CRS. In the long term, 2 patients from this group developed oncohematological diseases At an irradiation power of less than 0.001 Gy/day shallow thrombocytopenia and neutropenia are noted in the periods of outcomes and immediate consequences of CRS. In the period of long-term consequences, all the average values of peripheral blood indicators correspond to normal levels. Conclusions: With prolonged irradiation of a person with a dose rate of 0.008‒0.07 Gy/ day or more, with the accumulation of a total dose of 1.7‒9.6 Gy and a contact duration of 6‒96 months, one can expect the development of CRS with a peculiar subacute clinical course of bone marrow syndrome (BMS), manifested by the defeat of all three hematopoietic sprouts, the development of agranulocytosis, anemia and, probably, in 60 % of cases of leukemia development with an unfavorable prognosis for the patient’s life. The main factor determining this feature of the course of BMC CRS is the dose rate, which exceeds 0.008 Gy / day (2 Gr/year). At a dose rate of 0.003‒0.007 Gy / day (0.7‒1.7 Gy / year), the course of CRS with the development of agranulocytosis is possible in 25 %, anemia – in 33 % of observations. This course of the disease is most likely with a dose rate approaching the upper limit of the named range and high total doses. In other cases, the course of the disease is favorable. In the long-term period, moderate, transient leuko-, neutro- and thrombocytopenia are possible. With prolonged irradiation with a dose rate of less than 0.001 Gy / day (0.25 Gy / year), the course of the disease is relatively favorable with almost complete restoration of hematopoiesis in the long term.

D-index as a Risk Factor for Invasive Fungal Infections in Patients With Acute Lymphoblastic Leukemia From a Reference Hematology Center in Bogota.

Introduction Patients with hematologic malignancies are susceptible hosts for the development of invasive fungal infection (IFI), one of the main life-threatening infectious complications faced by these patients. Currently, we have antifungal prophylaxis strategiesand antifungal treatment schemes and we recognize that the main risk factor involved is profound and prolonged neutropenia. D-index and cumulative D-index are quantitative parameters, which determine the magnitude of neutropenia, as a function of duration and depth and their value correlates with the occurrence of IFI. Materialand methods A case-control study in patients older than 18 years with acute lymphoblastic leukemia (ALL) was admitted between 2009 and 2019 at the National Cancer Institute for induction, consolidationand salvage chemotherapy. Results A total of 167 patients were included, who received 288 cycles of chemotherapy, the latter were considered the unit of analysis. A generalized estimating equations (GEE) model was designed to analyze correlated data; three quantitative and continuous variables of interest were included in this model: age (years), D-index and deep neutropenia (days). For the population D-index, an odds ratio (OR) = 1.000227 (95% CI 1.0002-1.0004); p < 0.001 was obtained. Conclusion D-index is associated with the development of IFI in patients with ALL, with an exponential increase in OR as the absolute value of the D-index increases.

Acute Abdominal Complications in Deeply Neutropenic Onco-Hematology Patients: A Retrospective Series of 105 Cases.

Acute abdominal complications (AAC) in patients with deep neutropenia (DN) is challenging to manage because of the expected influence of AAC on oncological prognosis and higher surgical complication rate in a period of DN. In practice, these parameters are difficult to appreciate. This study reported our experience in managing these patients. All consecutive patients treated in our tertiary care cancer center between 2010 and 2020 who developed AAC in the context of a DN were retrospectively analyzed. AAC was defined as an infection (intra-abdominal, perineal, or cutaneous), bowel obstruction, or intra-abdominal hemorrhage. Among 105 patients, 18 (17%) required emergent surgery (group 1), 34 patients had a complication requiring surgical oversight (group 2), and 53 patients had a non-surgical etiology (group 3). Fifteen patients underwent surgery in the group 1, three in group 2, and one in group 3. Overall, 28 patients died during hospitalization. Mortality was statistically different between the groups (p = 0·01), with a higher rate in group 1 (n = 9/18, 50%) than in group 2 (n = 11/34, 32%) and group 3 (n = 8/53, 15%). All groups together had a median overall survival (OS) of 14months and disease-free survival (DFS) of 10months. OS was not comparable between the groups, and the median length of survival in group 1 was 6months versus 8months in group 2 and 23months in group 3. In group 1, five patients (5/18, 28%) did not relapse at the end of the follow-up compared to 13 in group 2 (13/34, 38%) and 25 in group 3 (25/53, 47%). After discharge, OS and DFS were similar between the groups. The advent of an AAC necessitating surgery in the context of DN is a deadly event associated with a 50% mortality; nonetheless, in case of unpostponable emergencies, surgery can provide long-term survival in selected patients.

Experience with the Use of B-RAF Inhibitor Vemurafenib in the Treatment of Hairy Cell Leukemia

Background. The standard and effective treatment of hairy cell leukemia (HCL) involves purine analogs, interferon-а (IFN-а) administration, and splenectomy. However, primary resistant HCL and early relapses (within 2-3 years after achieving remission) remain clinical challenges. Due to myelotoxicity of cladribine and slow effect of IFN-а, these drugs can be administered neither in deep neutropenia/agranulocytosis patients (especially in case of infectious complications) nor in patients with IFN-а allergy/intolerance. Aim. To report clinical experience with vemurafenib, a B-RAF inhibitor, in HCL with BRAFV600E mutation in treatment-resistant patients with contraindications to standard therapy. Materials &amp; Methods. The study enrolled 39 HCL patients aged 24-78 years (median 55 years), 13 women and 26 men. HCL was diagnosed in accordance with the WHO 2017 criteria. Vemurafenib 240 mg was administered once or twice a day within 3 months. Three groups of patients were analyzed: those with early relapses and resistant HCL (n = 7), those with deep neutropenia/agranulocytosis (with and without infectious complications, n = 29), and those with IFN-а intolerance (n = 3). Results. In 6 (86 %) out of 7 patients from group 1 (with early relapses and resistant HCL) a complete course of treatment was carried out, which included vemurafenib with subsequent standard cladribine chemotherapy and further consolidation with rituximab. Complete remission was achieved in 5 (71 %) patients, and partial remission was achieved in 1 (14 %) patient. The 7th patient was a non- responder. In 28 (97 %) out of 29 patients from group 2 with deep neutropenia/agranulocytosis, hematologic recovery was reported which allowed for further basic treatment with cladribine. In 1 patient vemurafenib appeared to be ineffective. In 3 patients from group 3 with IFN-а intolerance, vemurafenib administration was used as a stage of treatment preceding cladribine therapy. Cladribine treatment resulted in complete remission in 2 (67 %) patients and partial remission in 1 (33 %) patient. Conclusion. In HCL with BRAFV600E mutation, low-dose vemurafenib can be effective in patients with relapsed/refrac- tory disease as well as deep neutropenia with life-threatening infectious complications. In addition to that, vemurafenib administration can be used in cases of IFN-а intolerance as a stage of treatment of HCL with BRAFV600E mutation which precedes the basic cladribine therapy.

PONATINIB EXPERIENCE IN A PEDIATRIC CHRONIC MYELOID LEUKEMIA PATIENT

Chronic myeloid leukemia (CML) is rarely seen in children. The development of myelofibrosis in CML is not uncommon and is associated with a poor prognosis. In cases unresponsive to treatment, tyrosine kinase mutation should be checked for drug resistance, second generation tyrosine kinase inhibitor (TKI) drugs (dasatinib/nilotinib) should be switched to and a suitable donor for bone marrow transplantation should be sought. Third-choice TKI can be used in children who are unresponsive to treatment and do not have a suitable donor. Experience of third-choice TKI(ponatinib) in a child with CML diagnosis due to unresponsiveness to treatment. A 5.5-year-old female patient with no known disease was referred to us because of hepatosplenomegaly (liver 5 cm, spleen 10 cm). There was no laboratory disorder except for anemia (hgb 8.9 g/dL) and high LDH (1104 U/L). WBC was 11.1 × 10 3 /µL neu 6.92 × 103/ µL plt 304000/µL. Peripheral smear showed leukoerythroblastosis. Bone marrow biopsy result was evaluated as compatible with myelofibrosis and an increase in blast rate from 8% to 18% in the bone marrow. The patient was diagnosed CML accelerated phase with cytogenetic (46,XX,t(9:22)(q34;q11))and translocation (t(9:22)- p210,BCR/ABL positive) results and. Imatinib treatment was started at 400 mg/m 2 .The copy number of BCR-ABL p210 checked before treatment was 72% IS. However, the patient developed febrile neutropenia, and imatinib dose reduction (< 200 mg/m 2 ) and interruption were required in the follow-up.Under imatinib treatment, BCR-ABL copy number was 16%IS at 1 month, 11%IS at 3 months, and 95%IS at 5 months. Due to the increase in the BCR-ABL copy number, nilotinib was switched to as a second-choice TKI(230 g/m2/dose, in 2 doses).No mutation could be detected in the c-ABL gene, which was examined for tyrosine kinase resistance. HLA groups were sent from the family and compatible donors were not found. Due to severe neutropenia in the follow-up, nilotinib could be continued at 50% dose. Under nilotinib treatment, the BCR-ABL copy number was 13% IS at 1 month, 10% IS at 2 months, and 31% IS at 3 months. The patient was started on ponatinib (18 mg/m 2 /day) as a third choice TKI. However, due to the deep neutropenia of the patient, it was possible to continue with a dose of 10 mg/m 2 from the 2nd week. With this dose, the neutrophil is around 0.8-1 × 10 3 /µL. Under ponatinib treatment, BCR-ABL copy number was 6.6% IS at 1 month, 0.8% IS at 3 months, 0.09% at 5 months, and 0.05% at 6 months. No significant side effects were observed except neutropenia. There is no approved treatment in pediatric CML cases where the second choice TKI fails and there is no donor for transplantation. FDA approval for ponatinib in adult patients was obtained in December 2020. Ponatinib is a natural or mutant pan-BCR-ABL mutation inhibitor. It also inhibits VEGFR, FGFR,PDGFR,EPH and SRC kinases as well as KIT,RET,TIE2 and FLT3. The use of ponatinib should be evaluated by monitoring side effects/tolerance in pediatric cases where there is no other treatment option, and there is a need for studies on this subject.

Immune Reconstitution Inflammatory Syndrome Associated with Hepatosplenic Candidiasis in a Patient with Acute Myeloblastic Leukemia: Possible Pathogenesis and Treatment in the Light of Current Knowledge

Acquired immune deficiencies caused by different etiologies, promote invasive fungal infections. When this immunity begins to improve, it can induce an excessive inflammatory response defined as Immune Reconstitution Inflammatory Syndrome (IRIS). Hepatosplenic Candidiasis (HSC) can be considered a form of IRIS syndrome as it occurs following neutrophil recovery in patients treated for acute leukemia. Differentiating IRIS from a single fungal infection or treatment failure due to a similar clinical picture is a real diagnostic problem. Misdiagnosis and subsequently ineffective treatment with antifungal therapy instead of anti-inflammatory drugs, may lead fatal course of the disease. A deep and prolonged neutropenia developed after the first induction chemotherapy in our two and a half-year-old male patient who was followed up in our clinic with the diagnosis of Acute Myeloblastic Leukemia (AML). Our patient had fever, abdominal pain as well as his Gamma Glutamyl Transferase (GGT) and Alkaline Phosphatase (ALP) levels increased during neutropenia recovery. He was diagnosed with hepatosplenic candidiasis, by observing ‘target like abscesses’ on dynamic Magnetic Resonance Imaging (MRI) taken for his newly developing symptoms and laboratory findings while recovering neutropenia. After his first and third induction chemotherapy courses, his fever persisted although antifungal therapy, steroid treatment was initiated considering IRIS. After his re-intensification course, because of the same flare-up symptoms, we started immunglobulin in addition to steroid. With methylprednisolone and intravenous immunoglobulin, his symptoms improved and significant regression was observed in the lesions ‘target-like abscesses’ on MRI and in the laboratory values. Result: IRIS should be considered for patients with hepatic candidiasis whose have persistent fever despite appropriate antifungal therapy. Glucocorticoid should be started first for an anti-inflammatory effect.

Ibrutinib: A Risk Factor for Invasive Fungal Infections?

Background : Invasive fungal infections (IFI) are life threatening infections reported mainly in acute leukemia patients with prolonged deep neutropenia and patients post bone marrow or organ transplants.IFI are an uncommon consequence of CLL and NHL, cranial (brain, sinuses) involvement is distinctly rare. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. The Italian SEIFEM group reported the frequency of IFI in a retrospective multicenter study of CLL patients as 4 per 1104 patients over 5 years and among patients with NHL 27 per 3457 over 5 years. In a report combining 8 European countries, only 10 cases of CNS aspergillosis were identified in non-neutropenic ICU patients, between the years 2006-2011.Ibrutinib is a kinase inhibitor effective in the treatment of CLL and other NHLs has also been shown to have inhibitory activity against macrophages essential for defense against molds and Cryptococcus species.In 2016 we described 3 non-neutropenic CLL patients who developed invasive cranial aspergillosis while on treatment with ibrutinib (NEJM, 2016). In all three patients this developed shortly after beginning therapy with ibrutinib. All were on steroids before starting therapy and the course was fulminant. In two of the three patients the infection was fatal.Recently Lionakis et al (Cancer Cell, 2017) reported invasive aspergillosis in seven of 18 (39%) PCNSL patients treated with ibrutinib. Sites of involvement were cranial, pulmonary or both. None had prolonged neutropenia. The authors suggest that ibrutinib impairs fungal immune surveillance which may be exacerbated by the combined use of steroids and/or chemotherapy.In order to better understand if these cases were isolated events or connected to therapy with ibrutinib, in this retrospective, investigator initiated international study we summarize the clinical and laboratory parameters of patients who developed invasive fungal infections while being treated with ibrutinib.Methods : Patients with IFI were identified by treating physicians. Clinical and laboratory data were collected and managed using REDCap electronic data capture tools hosted at Shaare-Zedek Medical Center1(doi:10.1016/j.jbi.2008.08.010). The study received an IRB approval.Results : Twenty-eight patients with IFI were enrolled from 15 centers in 6 countries by 18 physicians (Table 1). The median age at the start of ibrutinib treatment was 71, and 71% had CLL. The median number of prior therapies was 3. Six out of 11 (54%) of patients with FISH results had 17pdel/ TP53 mutations. Twenty patients (71%) had at least 1 predisposing factor, 36% were treated with steroids when starting ibrutinib and three patients were post bone marrow transplants. The median lowest neutrophil count in the month before starting ibrutinib was 1.5 x 103/µl. Aspergillus was the main pathogen (64% of the cases), the main site being the lungs (75%) and cranial (brain, sinuses) in 57%. Six patients had multiple sites of involvement. The diagnosis of the pathogen was definite in 25 (89%) and probable in 11%. IFI resolved in only 25% of patients and mortality was 61% from all causes.Discussion : This cohort of 28 patients developed IFI on therapy with ibrutinib in the absence of common risk factors. Other unique features of our cohort are the high prevalence of CNS involvement (almost half of the patients); and the presentation of Aspergillus and Mucor ycosis spp infections at multiple sites, which is not a typical presentation for these pathogens. As the differential diagnosis was wide, most patients went through an invasive diagnostic procedure and therefore a high rate of a definite diagnosis was achieved rapidly in comparison to acute leukemia patients. Our preliminary results suggest that ibrutinib might be a risk factor for IFI resulting in unique patterns of clinical presentations. Subsequent comparative studies are urgently needed to better identify which patients on ibrutinib treatment are at greater risk for IFI. [Display omitted] DisclosuresBrown:Astellas Pharma: Consultancy; Sun BioPharma: Consultancy, Research Funding; Redx: Consultancy; Infinity Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy; Janssen Oncology: Honoraria; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding. Nijland:Novartis Pharmaeuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; MIllennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria.

Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy

BackgroundAdoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning...

Biosimilar of Rituximab for the Treatment of Primary Immune Thrombocytopenic Purpura : A Case-Control Study

INTRODUCTION Despite their daily use in the treatment of Thrombocytopenic Purpura Immunologic (ITP), rituximab biosimilars have never been evaluated directly in this indication. Our objective was to compare the efficacy and the tolerance of Rixathon ©, systematically used in our structure since April 2018, Mabthera © at adult patients with primary ITP. PATIENTS AND METHODS Medical records of the patients treated with Rixathon © for a primary ITP in our structure until December 31, 2019 have been retrospectively analyzed. All of these patients were included in the safety analysis. Patients with ITP secondary to an active malignant hematologic condition, a well-established auto-immune systemic disease or an anti-phospholipid syndrome, as well as patients in whom another ITP treatment was introduced within 8 weeks before or after the first injection of biosimilar, were excluded from the efficacy analysis. Rituximab-naive patients and those who had already received it in the past were separated into two groups. Naive patients were compared with controls from the registry "ITP-Ritux "which contains data from 248 patients treated with Mabthera © for a primary ITP. Rituximab non-naive patients were their own control. For the efficacy analysis, the primary endpoint used was the initial response to treatment, defined according to international criteria. A complete response corresponded to a platelet count&amp;gt; 100 G / L, a partial response to a level&amp;gt; 30 G / L with a doubling of the platelet count from the level before the injection. All other situations were considered as failures. For the safety analysis, all side effects, whether immediate or delayed, were collected. RESULTS A total of 38 patients treated with Rixathon © for ITP were included in the safety analysis. Of these patients, 26 (68%) were rituximab naïve and 6 (16%) had secondary ITP. The majority of patients were women (n = 28, 74%). Most of them were in the chronic stage of ITP (n = 24, 63%). Only 2 (5%) of the patients had undergone splenectomy. The median duration of follow-up was 6 months [IQR 3-12.5 months]. Of the 22 naive patients included in the efficacy study, 7 (32%) had a complete response and 8 (36%) a partial response. The observed overall response rate was 68%, a rate comparable to that observed in the PTI-Ritux registry (61%). In the 10 non-naïve rituximab patients included in the efficacy analysis, 6 (60%) were in complete response and 2 (20%) in partial response, i.e. an overall response rate of 80% in patients who had previously all responded favorably to Mabthera ©. During follow-up, 6 (16%) patients required initiation of at least one other disease-modifying treatment for ITP. Regarding immediate tolerance, 3 (8%) patients had immediate side effects when starting treatment but none required stopping the infusion: one patient presented with hives, another with abdominal pain and finally a patient was hospitalized after the infusion for a flare-up of heart failure. Away from the infusion, transient deep neutropenia was observed in 2 of 12 patients who were not rituximab naive. One of these two patients developed sepsis requiring hospitalization. In addition, during follow-up, one patient presented with pulmonary embolism and another with chronic abdominal pain. CONCLUSION The short-term efficacy of Rixathon © appears to overlap with that of Mabthera © in the treatment of primary ITP in adults. Data on a larger scale, with a more prolonged follow-up, are being collected in order to confirm these encouraging data. Disclosures Mahevas: GSK:Research Funding.Michel:Alexion Pharmaceuticals:Consultancy;Bioverativ:Consultancy;Rigel:Consultancy.Godeau:LFB:Honoraria;Novartis:Honoraria;Amgen:Honoraria;Amgen:Research Funding.

IBCL-341: Inhibitor of B-RAFV600E Mutation in Hairy Cell Leukemia

Context: The use of standard therapy (ST) in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia (DN) or the development of infectious complications (IC). HCL patients who do not respond to ST present a special therapeutic problem. Objective: Vemurafenib has been used to treat resistant HCL since 2012. Vemurafenib does not have a myelotoxic effect and so can be used in therapy of HCL with DN, as well as in early relapse after ST or as a primary refractory course of HCL (RR). Design: The applicability of vemurafenib in patients with HCL with DN, including patients with IC and RR. Setting: Study setting can be used in hematological inpatient (including intensive care department) and outpatient departments. Patients: Vemurafenib was used in 27 patients with HCL (m: f = 2.4; median age 57 years (24–78 years): six RR patients and 21 patients with DN, including 7 patients with severe infectious manifestations in the intensive care department, including 1 patient on extracorporeal membrane oxygenation. Intervention: Vemurafenib was used in a dose of 240 mg 1–2 times a day. In 26 patients, vemurafenib was used for 3 months or more. Main Outcomes Measures: The response to therapy was evaluated by control of neutrophil count, size of the spleen, and resolution of the IC. Results: In patients with DN, the response was achieved in 95%, followed by 1 course of ST with cladribine. In 1 patient, within 1 month of vemurafenib therapy, the effect was not obtained. Among RR patients, 67% achieved remission of the disease after a course of therapy with vemurafenib for 3 months, followed by a ST of cladribine and maintenance therapy with rituximab or obinutuzumab. There were no complications with the use of vemurafenib. Short agranulocytosis within three days after the course of cladribine was observed in only two patients. Conclusion: Therapy of HCL patients with DN, IC, and RR is a complex therapeutic problem. In cases with proven BRAFV600E mutation, vemurafenib can be effectively used not only in RR patients but as an effective preliminary therapy in patients with DN and IN before a ST with purine analogues.

Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia

Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to β lactams. As expected, there were not non-susceptible strains to vancomycin. VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to β lactams is an issue that requires strict epidemiological surveillance in this population.

Assessment of Hematological Toxicity in Children with Acute Lymphoblastic Leukemia, Receiving Treatment with ALL IC-BFM 2009 Protocol

The most common childhood cancer is acute lymphoblastic leukemia (ALL). Chemotherapy-associated hematological toxicity is well-known; however, there are few studies on hematologic toxicity incidence in children with ALL. We investigated the severity and incidence of hematologic toxicity during intense chemotherapy processes in children treated with ALL IC-BFM 2009 protocol. The study included 41 leukemic children in standard (SR) and intermediate risk (IR) groups treated between 2011 and 2015. During the induction period, the incidence of grade 4 toxicity in neutrophil count was 60%; the incidence of grade ≥ 3 toxicity in hemoglobin level was 34%; and the incidence of grade ≥ 3 toxicity in the platelet count was 51%. Deep neutropenia duration was 36.6 ± 12.7 (18-68) days during the induction. 53% of the febrile neutropenic (FEN) episodes developed during the induction period. There were no statistical differences between SR and IR risk groups with respect to hemogram values deep neutropenia duration and the number of FEN episodes (p > 0.05, all). There was a positive correlation between the number of FEN episodes and duration of neutropenia. During the induction, the mean neutrophil count remained between 0.5-1 × 109/L. FEN episodes most commonly developed during the induction phase.

Chronic Disseminated Candidiasis Complicated by Immune Reconstitution Inflammatory Syndrome in Child with Acute Lymphoblastic Leukemia.

Hepatosplenic candidiasis also known as chronic disseminated candidiasis is a rare manifestation of invasive fungal infection typically observed in patients with acute leukemia in prolonged, deep neutropenia. Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory disorder triggered by rapid resolution of neutropenia. Diagnosis and treatment of IRIS are still challenging due to a variety of clinical symptoms, lack of certain diagnostic criteria, and no standards of treatment. The diagnosis of IRIS is even more difficult in patients with hematological malignancies complicated by “probable” invasive fungal infection, when fungal pathogen is still uncertain. We report a case of probable hepatic candidiasis in 4-year-old boy with acute lymphoblastic leukemia. Despite proper antifungal therapy, there was no clinical and radiological improvement, so diagnosis of Candida-related IRIS was made and corticosteroid therapy was added to antifungal treatment achieving prompt resolution of infection symptoms.

Invasive Fungal Infections in Acute Promyelocytic Leukemia Patients. Results of a Prospective Multicenter Study in Italy

OBJECTIVESAim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia.PATIENTS AND METHODSFrom January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases.RESULTS1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study.Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded.Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy.IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment.A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S.Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified.DISCUSSIONIn our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted. DisclosuresNo relevant conflicts of interest to declare.

New Translocation (7:17) In Variant Acute Promyelocytic Leukemia With ATRA Resistance

BackgroundAcute promyelocytic leukemia (APL) is characterized by pathologic promyelocytes, chromosomal translocations t(15:17) (q22; q21) and clinical and cytological response to all-transretinoic acid (ATRA). A significant minority of patients with APL have variant translocations involving RARα gene with a different partner, not involving PML. These APL variant translocations may or not respond to ATRA treatment. Case reportA routine laboratory evaluation, before minor surgery, revealed leukocytosis, thrombocytopenia and blasts presence in peripheral blood (PB), in an otherwise asymptomatic 70-year-old man. He had a previous history of hypertension, dyslipidemia, ischemic heart disease, double coronary bypass and prostatectomy for non-malignant prostatic hypertrophy.Peripheral blood (PB) count: hemoglobin concentration 12g/dL, platelet count: 21x109/L and white blood cell count (WBC): 35x109/L. Peripheral blood smear: myelemia exhibiting 74% blasts (including myeloid blast and promyelocytes) with fine chromatin pattern, heterogeneous and frequently convoluted nuclei and one to three prominent nucleoli. The cytoplasm of these cells was basophilic with scanty purple granules. No Auer rods were found. The basic coagulation tests were normal(INR, APTT and fibrinogen) but D Dimer was 33.87 µg/ml. Normal biochemistry was shown, except for GGT 85 U/L and lactate dehydrogenase 2244 U/L.Bone marrow (BM) aspirate was unsuccessful (”dry tap”) but the bone trephine revealed an infiltration of 80% myeloid blasts. Cytochemistry: myeloperoxidase stain was deeply positive and chloroacetate and non-specific esterase stains were negative. Flow cytometry immunophenotype on PB was consistent with AML, likely M3 leukemia, with an atypical phenotype (MPO+, CD117+low, CD34+, CD13++, CD45+, CD15-,CD133-, CD33+, HLA-DR+low het , CD5-, CD7-, CD11b- , CD56+het, CD10-, CD8-,CD4-, CD45RA+, CD19-, CD2-, Glya-, CD71+low, CD38-, CD1a-, CD41-, CD14-).The analysis of the PML/RARα fusion gene, according to standard protocols, was negative. FISH studies showed 2 PML signals and 3 RARα copies, suggesting a possible variant rearrangement of this gene. FISH and molecular biology did not detect transcript for t(15:17), (5:17) or (11:17); so RARα was translocated with a strange partner.Suspecting of a variant APL, the patient was treated with ATRA plus Idarrubicin. After 4 weeks treatment, deep neutropenia was observed but no granulocytic maturation. That suggested us resistance to ATRA. Thus, we changed the treatment to a classical induction scheme for AML. The patient attained cytologic remission, which he mantains so far with conventional chemotherapy.Karyotype study was subsequently performed, identified an unbalanced rearrangement between 7q and 17q. Currently, we are identifying and sequencing the fusion partner of RARα. ConclusionWe report a novel case of variant acute promyelocytic leukemia with the karyotype der (7) t(7;17) (q11;q21). The morphology of PB and BM was critical for initial diagnosis and treatment decisions. Disclosures:No relevant conflicts of interest to declare.

Incidence, risk factors, and outcome of bacteremia following autologous hematopoietic stem cell transplantation in 720 adult patients

Bacteremia is the most frequent infectious complication during neutropenia in patients receiving autologous hematopoietic stem cell transplantation (ASCT). The objective of this study was to analyze the incidence, characteristics, risk factors, and outcome of bacteremia during the early period after ASCT. A total of 720 patients undergoing ASCT in two observational prospective consecutive multicenter studies of the Programa Español para el Tratamiento de las Hemopatías group were analyzed. Bacteremia occurred in 20 % of patients. Coagulase-negative Staphylococcus was the most frequent (66 %) among the gram-positive agents and Escherichia coli (49 %) among the gram-negative agents. Multivariate analysis showed that the length of neutropenia <1 × 10(9)/L (more than 9 days) [relative risk (RR) of 2.6, p < 0.001] was the sole risk factor for overall bacteremia. We identified the length of neutropenia <1 × 10(9)/L (more than 9 days) (RR 4.98, p < 0.001) and the use of prophylactic fluoroquinolones (RR 0.46, p < 0.01) as specific risk factors for gram-negative bacteremia. Risk factors for gram-positive bacteremia were the use of total parenteral nutrition (RR 1.92, p < 0.01) and deep neutropenia (<0.1 × 10(9)/L), with duration over 5 days (RR 1.67, p < 0.027). Bacteremia showed an increased morbidity with no impact on neither overall nor infectious related mortality. The identification of such risk factors may be helpful to implement prophylactic and therapeutic risk-adapted strategies to reduce the incidence of bacteremia in ASCT.

Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC)

BackgroundTo assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. Patients and methodsTwenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3–6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3–4, thrombocytopenia grade 3–4 and non-hematological grade 3–4 events (secondary end points). ResultsCarriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). ConclusionGenetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

The impact of genetic variability on severe toxicity of (neo-) adjuvant chemotherapy in breast cancer patients receiving 5-fluorouracil, epirubicin, and cyclofosfamide (FEC).

1020 Background: We assessed the impact of single nucleotide polymorphisms (SNP) of potential genes of interest in germline DNA on severe adverse events in breast cancer (bc) patients receiving (neo-) adjuvant FEC chemotherapy. Methods: Cases were retrospectively evaluated through electronic chart review for febrile neutropenia (primary endpoint), febrile neutropenia first cycle, prolonged grade 4 or deep (&lt;100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events. The panel of genes, genotyped using iPLEX technology on a MALDI-TOF based MassARRAY Compact Analyser (Sequenom Inc., CA, USA), included ABCBI, ABCC1, ABCC2, ABCG2, ALDH3A1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, DPYD, FGFR4, GPX4, GSTA1, GSTP1, MTHFR, NQ01, TYMS, XPD/ERCC2, XRCC1, UGT1A1, UGT1A6 and UGT2B7. These genes are involved in the metabolization of the studied chemotherapeutics. Because of multiple testing the false discovery rate (FDR) was calculated. Results: We identified 1089 patients treated between 2000-2010 with 3-6 cycles of FEC, for whom germline DNA was available.Homozygous (TT, 0.5%) and heterozygous (GT,11%) genotypes for rs4148350 in the Multi Drug Resistance Protein I (ABCC1/MRP1), compared to wild-type (GG, 88.5%), were associated with febrile neutropenia, febrile neutropenia in first cycle, prolonged grade 4 or deep neutropenia and thrombocytopenia (80 vs 25 vs 15.7%, 40 vs 17.6 vs 9.5%, 100 vs 41.7 vs 33.8% and 20 vs 2.8 vs 0.34% respectively; p 0.0006, 0.01, 0.002 and 0.008 FDR 0.03, 0.65, 0.06 and 0.2). Variant genotypes for rs45511401 (GT/TT, 12%) in ABCC1, compared to wild-type (GG, 88%), were associated with febrile neutropenia, febrile neutropenia in first cycle and thrombocytopenia (26.5 vs 15,8%, 17.1 vs 9.7% and 3.4 vs 0.3%, respectively; p 0.007, 0.03 and 0.005, FDR 0.2, 0.75 and 0.2). Conclusions: Genetic variation in the ABCC1 gene was strongly associated with severe hematological toxicity of FEC. Other previously described SNP were not validated. This is the largest bc study in which the impact of genetic variability on the adverse events of FEC chemotherapy was investigated.

The importance of cleanrooms for the treatment of haemato-oncological patients.

The main purpose of cleanrooms in health care centres is to prevent hospital infections or leakage of a highly infectious agent (the source of haemorrhagic fevers, SARS, etc.) into the ambient environment and subsequently possibly threatening other individuals.Patients with haematological malignancies or after autologous or allogeneic haematopoietic stem cell transplantation (HSCT) rank among immunosuppressed individuals. Prolonged and deep neutropenia is considered a key risk factor of the occurrence of an exogenous infection. One of the possibilities of preventing an exogenous infection in these patients is to place them in a “cleanroom” for the crucial period of time. Cleanrooms are intensive care units with reverse isolation.The final part of the general article below provides an overview of the technology and types of cleanrooms for immunosuppressed patients in compliance with the current recommendations and technical standards.